IL-21 produced by CD4+ T cells drives differentiation of CD8+ T cells during polyomavirus encephalitis

Abstract

Abstract The demyelinating brain disease Progressive Multifocal Leukoencephalopathy (PML), caused by JC polyomavirus (JCV), is a life-threatening complication for patients with HIV/AIDS, hematologic malignancies, rheumatologic diseases, and those receiving long-term immunomodulating therapies. Using mouse polyomavirus (MuPyV), our laboratory developed a robust model of polyomavirus-associated demyelinating leukoencephalitis, complete with viral infection and T cell infiltration. Increasing evidence supports the importance of CD4+ T cells in controlling JCV in the brain and thereby preventing PML. Recent studies in our laboratory show that CD4+ T cells are essential for differentiation and maintenance of MuPyV-specific brain-resident memory CD8+ T cells (bTRM). We find that the help CD4+ T cells are provide to virus-specific CD8+ T cells for their appropriate bTRM differentiation is IL-21. PD-1hiCXCR5hi MuPyV-specific CD4+ T cells are the primary sources of brain IL-21 and co-localize with CD8+ T cells in the brain. Brain MuPyV-specific CD8+ T cells have increased expression of the IL-21 receptor (IL21R) 15 days post-infection, which correlates to the time-point when they begin to express CD103, a canonical TRM marker. TRM maintenance is independent of circulating cells. In line with this property, we show that MuPyV-specific CD8+ T cells are not depleted by parentally administered anti-CD8. In addition, brain CD8+ T cells from IL21R−/ − mice have decreased expression of CD103 and are susceptible to depletion from peripheral anti-CD8. These data indicate that during polyomavirus infection, IL-21 by CD4+ T cells drives CD8+ T cells to differentiate into tissue resident memory in the brain.